Fast variable gain detector system and method of controlling the same

ABSTRACT

A micro-channel plate (MCP) detector system ( 30 ) comprising a MCP detector, a data acquisition unit ( 20 ), wherein the detector comprises a first and a second MCP electron multiplier ( 12, 14 ), one or more anodes ( 16 ) connected to the data acquisition unit ( 20 ) and a gate electrode ( 32 ) disposed between the first and the second MCP electron multiplier ( 12, 14 ), wherein the detector system further comprises a data storage unit ( 36 ) and a gain control unit ( 34 ) which is connected to the gate electrode ( 32 ) and to the data storage unit ( 36 ), wherein a pilot spectrum is stored in the data storage unit ( 36 ), and wherein the gain control unit ( 34 ) is arranged to read the pilot spectrum from the data storage unit ( 36 ), and to control the potential on the gate electrode ( 32 ) as a function of m/z or time in response to said pilot spectrum, such that the transmission of electrons to the second MCP electron multiplier ( 14 ) is lowered when abundant protein ions appear, whereby a high sensitivity is maintained during the remainder of the measurement cycle such that neighboring peaks from rare protein ions become detectable.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a filing under 35 U.S.C. §371 and claims priority tointernational patent application number PCT/EP02/04886 filed May 3,2002, published on Nov. 14, 2002 as WO02/091425, and to foreignapplication number 0101555.1 filed in Sweden on May 4, 2001, the entiredisclosures of which are hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to a micro-channel plate (MCP) detectorsystem, a modified fast gain MCP-detector and a method of operating thesame. More specifically, the invention relates to a micro-channel platedetector system with fast variable gain and a method of operating thesame, such that an improved dynamic range is achieved.

PRIOR ART

Analyzing all proteins from cells is impossible by today's techniquessince the amount of each expressed protein varies over a huge dynamicrange. Mass spectrometry, together with other techniques, has shown alack of the necessary dynamic range, largely due to lack of a detectiontechnique that can detect both the abundant and the very rare proteinswithin the same mixture. Noteworthy is, that also a separated (LC, gel,etc) sample will display mixtures with overlapping protein species, sothe problem with complex mixtures remains also after separation. Anideal mass spectrometer should therefore have single particlesensitivity and a high dynamic range. FIG. 3a shows a fabricated exampleof a mass spectrometer spectrum, wherein these large variations inamount of each expressed protein are illustrated.

In this document ionization efficiency and transmission from ion sourceto detector will not be discussed. Designing a mass spectrometricdetection is a trade off. Today, a perfect system can only be designedto one of the two extremes: either tailoring the detection forsingle-ion detection or for high dynamic range. The extreme sensitivitycan be achieved by using a high detector gain and digitalsingle-particle pulse counting electronics. High dynamic range can beachieved by using lower gain and analog detection electronics. Theproblem is that, ideally, both the high sensitivity and the high dynamicrange are wanted.

FIG. 1 shows a micro-channel plate (MCP) detector system 10 for a massspectrometer. A micro channel plate multiplier 12, 14 consists of alarge number of individual electron multiplier channels positioned inparallel typically in the shape of a perforated thin dish. Such adetector system typically comprises two MCP electron multipliers 12, 14,each having a gain of approximately 1000. This means that the first MCP12 converts the incident ion 18 to a number of secondary electrons,which are then further multiplied to give of the order of 1000 electronsat the exit of this first detector. These 1000 electrons are transportedto the second MCP 14 situated of the order of millimeters away. The 1000electrons will impinge on the surface of the second MCP 14, and a newmultiplication process with an amplification of approximately 1000 takesplace.

The amplification of the MCP will be temporary degraded (or lost) if toomany secondary electrons are drawn from the output of a channel. Thedegraded gain results in lowered signal-to-noise ratio in the recordedspectrum when using analog-to-digital conversion (ADC) or a dead timeafter a large peak when using time-to-digital conversion (TDC).Temporary degradation of the gain occurs under two circumstances, eitherwhen the gain is high (which is needed for high sensitivity) or when toomany ions reaches the MCP within a short period of time (which may bethe case for certain ion species in high dynamic range mode).

Therefore it is obvious that trying to detect a sample with largevariations of protein concentrations will give rise to just theseconditions. In the high gain mode, the rare proteins will be lost sincethey drown in the highly attenuated signal from the abundant proteins.In the low gain mode, the signal from the rare proteins will be lostsince it is too close to the dark current (signal with ion beam turnedoff) of the MCP.

Hence, there is needed a method that combines the best sides of the lowgain and the high gain mode of operating the MCP detector system. Therehave been shown several ways to provide detector systems having anextended dynamic range.

A detector of this type which has two modes of operation to extend itsdynamic range is disclosed by Kristo and Enke in Rev. Sci. Instrum. 1988vol 59 (3) pp 438-442. This detector comprises two channel type electronmultipliers in series together with an intermediate anode. Theintermediate anode was arranged to intercept approximately 90% of theelectrons leaving the first multiplier and to allow the remainder toenter the second multiplier. An analogue amplifier was connected to theintermediate anode and a discriminator and pulse counter connected to anelectrode disposed to receive electrons leaving the second multiplier.The outputs of the analogue amplifier and the pulse counter wereelectronically combined. A protection grid was also disposed between themultipliers. At high incident ion fluxes, the output signal comprisedthe output of the analogue amplifier connected to the intermediateanode. Under these conditions a potential was applied to the protectiongrid to prevent electrons entering the second multiplier (which mightotherwise cause damage to the second multiplier). At low ion fluxes, thepotential on the protection grid was turned off and the output signalcomprised the output of the pulse counter. In this mode the detector wasoperable in a low sensitivity analogue mode using the intermediate anodeand a high sensitivity ion counting mode using both multipliers and thepulse counter, so that the dynamic range was considerably wider than aconventional detector which only use one of these modes. The switchingbetween the two sensitivity levels is in this case performed as aresponse to the detected signal, i.e. direct feed back.

WO 99/38190 disclose a dual gain detector having two collectionelectrodes with different areas, whereby the larger electrode is usedfor detecting at low ion flux and the smaller at high ion flux. In aspecial embodiment the smaller collection electrode is provided as agrid that is placed between the first and the second MCP.

Soviet Inventors Certificate SU 851549 teaches the disposition of acontrol grid between two micro channel plate electron multipliers, thepotential of which can be adjusted to control the gain of the assembly.This detector is further incorporated in a direct feed back detectionsystem.

However, none of these detector systems represent a system that has theability to cover the complete ion flux spectra of the proteins in a cellwith high accuracy. More specifically, Kristo et al only detects approx.10% of the ions at low ion fluxes, and both this system and the systemdisclosed in WO 99/38190 represent static two level systems, whichresults in lower over all sensitivity.

SUMMARY OF THE INVENTION

Obviously an improved detector system is needed, which providesdetection over an improved dynamic range, such that analysis of sampleswith large variations of protein concentrations, e.g. a cell, may beperformed with a mass spectrometer.

The object of the present invention therefore is to provide a new highsensitivity detector system and a method of controlling the same, whichovercome the limitations with the prior art devices. This is achieved bythe detector system of claim 5 by the method as defined in claim 1 andby the detector of claim 3.

An advantage with the detector system according to the invention is thata new detector system with fast variable gain and a method of operatingthe same are achieved.

Embodiments of the invention are defined in the dependent claims.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows an example of a conventional MCP detector system.

FIG. 2 shows a fast switching MCP detector system according to theinvention.

FIGS. 3a-3 c show examples of recorded spectra at different steps of themethod according to the invention.

FIG. 4 shows a fast switching MCP detector according to one embodimentof the invention.

DETAILED DESCRIPTION OF THE INVENTION

Embodiments of the invention will now be described with reference to thefigures.

FIG. 2 shows the detector system 30 according to the invention, which iscomprised of a modified MCP detector which will be described in detailbelow, a data acquisition unit 20, a data storage unit 36 and a gaincontrol unit 34. The data acquisition 20 unit is connected to thedetector anode 16 and provides spectrum data to the data storage unit 36and/or to an external data processing unit for processing andpresentation of acquired spectra The gain control unit 34 is arranged tocontrol the gain of the detector during the acquisition of a spectra inaccordance with a control spectra stored in the data storage unit 36,which control spectra may resemble a previous recorded pilot spectra oranother predefined spectra.

The basic idea behind the invention is to lower the detector gain bylowering the transmission to the second MCP 14 when abundant proteinions appear. This change of overall gain has to be performed during thearrival time of the ion (mass spectral peak width), that is, at a timescale of about 10 ns for time-of-flight systems. Due to this extremelyshort time scale the gain can not be varied by changing the voltage overthe MCP 12, 14 in a conventional MCP detector, since the 1GΩ resistanceof the MCP 12, 14 will make the electric-field drop over the MCPchannels a timely event.

Instead, as shown in FIG. 2, a modified MCP detector is proposed. Themodified MCP detector will hereafter be referred to as a fast variablegain MCP detector, and just like a conventional MCP detector itcomprises a first and a second MCP 12, 14, and an anode 16 forcollecting the output electrons from the second MCP 14. A fast variablegain MCP detector may then be achieved by disposing a gate electrode 32between the first and the second MCP 12, 14. The gate electrode 32,which could be a high transmission conductive mesh, may provide aretarding field to the output electrons from the first MCP 12. Theretarding field then causes the electrons with low energy to be retardedand turned back, while the high-energy part of the output electronenergy distribution passes through the gate electrode, whereby alowere-electron current reaches the second MCP 14. The anode 16 collectsthe output electrons from the second MCP 14, and due to the retardingpotential at the gate electrode 32 the output signal from the anode 16is lowered. The working principals of the detector will now be similarto the operation principle of the predecessor to the transistor, thetriode electron tube. In this analogy, the first MCP 12 acts as thecathode, the gate 32 as the grid, and the second MCP 14 and anode 16 asthe anode of the electron tube.

In the MCP detection system according to the invention, the gain controlunit 34 is connected to the gate electrode 32, whereby it may controlthe gain of the fast variable gain MCP detector by applying anappropriate retarding potential on the gate electrode 32. As mentionedabove the gain control unit 34 receives control information data fromthe data storage unit 36.

To know when to lower the gain for a certain sample a first “pilot”spectrum is recorded for the sample by performing a measurement with aconstant potential on the gate electrode 32. The recorded pilot spectrumis thereafter stored in the data storage unit 36. An example of such apilot spectrum is shown in FIG. 3a, and examples of spectra that areobtained in later steps of the method is shown in FIGS. 3b and 3 c. Insome cases the pilot spectrum may advantageously be recorded with apotential on the gate electrode 32 that varies according to apredetermined function.

During the following measurement cycle(s) the gain control unit 34receives the pilot spectrum from the data storage unit 36, and inresponse to this spectrum it applies a retarding potential as a functionof m/z or time on the gate electrode 32 (FIG. 3b). Whereby, the recordedspectrum from the following measurement cycle(s) is, so to say,modulated with the stored pilot spectrum, and faint peaks may appear. Ascan be seen in FIG. 3c, this process causes the second peak to appear,which peak was highly discriminated in the first spectrum (FIG. 3a), andthe initially high peak in the pilot spectrum is lowered due to thelower gain at this m/z.

To further improve the accuracy, several spectra may be summed up toobtain a better signal-to-noise (S/N) ratio, and this summed spectrummay then be used as a new pilot spectrum. Where after this process isrepeated until the sample is consumed, or enough information isgathered.

In cases when a well-known sample is to be analyzed, and when only asmall sample volume is available, a predefined pilot spectrum may beused, and the recording of a pilot spectrum may be omitted. In this way,pilot spectra only have to be recorded when an unknown sample is to beanalyzed.

In an alternative embodiment of the fast variable gain MCP detector, ashielding electrode 40 may be displaced between the first MCP 12 and thegate electrode 32 to shield the retarding potential on the gateelectrode 32 and give shorter response time and peak broadening.Alternatively a second shielding electrode 42 may also be displacedbetween the gate electrode 32 and the second MCP 14, whereby even betterperformance is achieved. As the detector in general, as mentioned, issimilar to triode electron tubes, alternative embodiments, correspondingto existing electron tube configurations, are to be considered to bewithin the scope of the present invention.

The first MCP 12 may perform a direct conversion of the incident ions 18to secondary electrons, or alternatively, a separate conversion dynodesurface (not shown) may be introduced into the system prior to the firstMCP 12 where the ions impinge and produce secondary electrons forfurther transport to the first MCP 12. In this second version, the gateelectrode 32 may be introduced either between the first and second MCP12, 14, or between the conversion dynode and the first MCP 12. Extraelectrodes may be introduced for acceleration of the electrons and forshielding of electrical fields.

It is also conceivable, to allow better detection of rare ions, togradually increase the voltage over the MCP (U_(MCP)) between spectra,thus enhancing the non-gated gain of the MCP. To make this effective, itis essential to modulate the gate potential within each spectrum todiscriminate the abundant ions.

It would be possible to use both ADC and TDC techniques, using ADC forhigh abundance ions and TDC for the lowest abundance ions. The ADC canbe used to mimic a TDC using fast data processing between each spectrum.It will be advantageous to use a variable discriminator circuit or biasthreshold for the TDC/ADC techniques, so that the discriminator or biasthreshold levels can be varied between spectra.

What is claimed is:
 1. A method of acquiring a wide dynamic rangespectrum using a fast switching micro-channel plate (MCP) detectorincluding a gate electrode (32) disposed between a first and a secondMCP electron multiplier (12, 14), comprising the step of: applying, inresponse to a pilot spectrum, a retarding potential as a function of m/zor time on the gate electrode (32), such that the transmission ofelectrons from the first MCP (12) to the second MCP electron multiplier(14) is lowered when abundant protein ions appear and neighboring peaksfrom rare protein ions may be detectable.
 2. The method of claim 1,wherein the pilot spectrum is achieved by the steps: acquiring a firstspectrum with the potential on the gate electrode (32) set to a constantvalue or set to follow a predetermined function throughout themeasurement cycle, and saving the first acquired spectra as the pilotspectra.
 3. A fast switching micro-channel plate (MCP) detectorcomprising a first and a second MCP electron multiplier (12, 14), ananode (16), and a gate electrode (32) that is disposed between the firstand the second MCP electron multiplier (12, 14), wherein a shieldingelectrode (40) is displaced between the first MCP electron multiplier(12) and the gate electrode (32) to shield the retarding potential onthe gate electrode (32).
 4. The MCP detector of claim 3, wherein asecond shielding electrode (42) is displaced between the gate electrode(32) and the second MCP electron multiplier (14) to further shield theretarding potential on the gate electrode (32).
 5. A micro-channel plate(MCP) detector system (10) comprising a MCP detector, a data acquisitionunit (20), wherein the detector comprises a first and a second MCPelectron multiplier (12, 14), one or more anodes (16) connected to thedata acquisition unit (20) and a gate electrode (32) disposed betweenthe first and the second MCP electron multiplier (12, 14), wherein thedetector system further comprises a data storage unit (36) and a gaincontrol unit (34) which is connected to the gate electrode (32) and tothe data storage unit (36), a pilot spectrum is stored in the datastorage unit (36), and the gain control unit (34) is arranged to readthe pilot spectrum from the data storage unit (36), and to control thepotential on the gate electrode (32) as a function of m/z or time inresponse to said pilot spectrum, such that the transmission of electronsto the second MCP electron multiplier (14) is lowered at the time thatit is expected that abundant protein ions will appear, whereby a highsensitivity is maintained during the remainder of the measurement cyclesuch that neighboring peaks from rare protein ions become detectable. 6.The mass-spectrometer of claim 5, further comprising a micro-channelplate (MCP) detector system (10).